This is the second re-submission (A2) of competing renewal application 2R01MH062527. This application focuses on the neurobiology of cognitive symptoms of schizophrenia that are not well treated by available medications. Administration of the NMDA receptor antagonist phencyclidine (PCP) to humans evokes several schizophrenia-like effects, including cognitive deficits, observed only during PCP intoxication. In the proposed rat studies, the inducing condition will be a repeated PCP administration regimen that induces deficits in various cognitive functions that are relevant to schizophrenia (attention/vigilance, working memory, reasoning/problem solving, speed of processing, as identified by the NIMH-FDA collaborative MATRICS program), and alterations in glutamate and GABA system function implicated in schizophrenia neuropathology. Specifically, the effects of the repeated PCP administration regimen will be assessed in: a) the 5-choice serial reaction time task (5-CSRTT) that assesses attention and inhibition of inappropriate responding, corresponding to the attention and reasoning/problem solving domains, respectively; b) the discrete paired-trial variable-delay alternation task that assesses the working memory domain; and c) the cued-location reversal learning task that assesses cognitive flexibility, an aspect of the reasoning/problem solving domain. All tasks also assess the speed of processing domain. Specific Aim 1 will examine how three atypical antipsychotics, with different receptor affinity profiles and differential effects on cognitive measures in humans, alter PCP-induced deficits in the proposed cognitive tasks. Our extensive Preliminary Studies showed that clozapine, but not quetiapine, partially attenuated repeated PCP-induced deficits in attention and response inhibition in the 5-CSRTT, demonstrating that the study of the effects of antipsychotics with variable receptor profiles on cognitive tasks may provide information about neurotransmitters/receptors involved in some, but not other, cognitive deficits. Specific Aim 2 will investigate neurochemical correlates of PCP-induced cognitive deficits and their potential reversal by these atypical antipsychotics by using in vivo microdialysis to measure monoamine, glutamate, and GABA levels in the prefrontal cortex and the nucleus accumbens. These brain sites are implicated in schizophrenia pathology and performance in the proposed cognitive tasks. Finally, Specific Aim 3 will explore whether experimental pharmacological treatments probing specific neurotransmitter and receptor systems, including serotonin, norepinephrine, glutamate, and GABA, may reverse PCP-induced cognitive deficits. These treatments will be guided by the results of the dialysis studies. In summary, a multidisciplinary integrated experimental approach using behavioral, neurochemical, and pharmacological techniques will investigate the neuromechanisms underlying the cognitive deficits of schizophrenia, and specific transmitter actions of atypical antipsychotics that may mediate their differential effects on various cognitive domains. This work will aid in the discovery of novel therapeutic targets for these cognitive deficits. Schizophrenia is a chronic mental illness that results in tremendous human suffering and monetary costs to society. Cognitive impairments are core symptoms of schizophrenia that are not adequately treated by available medications and greatly contribute to profound functional impairment. The results of the proposed studies will promote our understanding of the neurobiology of cognitive deficits in schizophrenia, will elucidate specific neurotransmitter actions of atypical antipsychotics that may mediate their differential effects on various cognitive domains, and finally aid in the discovery of novel therapeutic targets for these poorly treated cognitive deficits.